Medulloblastoma (MB) represents the most common childhood malignant brain tumor. Even though 60-70% of children with non-metastasized MB have a five-year survival rate after aggressive multimodal therapy, including surgery, radiotherapy, and chemotherapy, a significant proportion of surviving patients suffer from severe treatment-related side effects, especially from leukoencephalopathy and cognitive deficits, and often have tumor relapse. This presents an urgent need for novel therapeutic modalities that can improve MB patient survival while minimizing adverse side effects. Activation of either the Sonic Hedgehog (SHH) pathway or the WNT signaling pathway is found in about 40% of human MBs, critical for the initiation and growth of MB, and a prime therapeutic target for treating patients with MBs. Although the outlook for MB therapy with Shh inhibitors is promising, drug resistance and side effects can occur, thus presenting a roadblock to the prospect of Shh pathway inhibitors in advancing MB therapy. Identifying and targeting key pathways that are vital to MB growth is essential to overcoming this challenge. While investigating the role of the G-protein coupled receptor signaling pathway in brain development, strikingly, we found that mice with GS alpha alleles ablated in neural stem/progenitor cells developed MB with 100% penetrance. Our preliminary studies indicate that mice with GS alpha deletion developed two major subtypes of MBs, SHH- and WNT- subtypes, depending on the cellular context. Transplantation of freshly isolated tumor cells from GS alpha mutants produced MB-like tumors in xenograft mice. Collectively, we have established a novel animal model of MB, where GS alpha ablation in anatomically distinct neural precursor cells gives rise to different subtypes of MBs. We hypothesize that GS alpha signaling orchestrates Shh and Wnt signaling pathways in MB formation, and may serve as a potential therapeutic target for MB treatment. We will first determine the progenitor cell types that are competent to form MBs induced by GS alpha mutation. Second, we will identify define the critical downstream pathways that drive tumorigenesis in GS alpha mutants. Third, we will test the hypothesis that MB formation induced by GS alpha deletion requires activation of Shh and Wnt signaling pathways by genetic and pharmacological approaches. Thus, these proposed studies will advance our understanding of the pathogenesis and treatment of MB at molecular and cellular levels should facilitate devising new, effective strategies to treat these deadly pediatric brain cancers. PUBLIC HEALTH RELEVANCE: The work proposed in research plans will provide better understanding of cancer pathways and critical signals that drive tumorigenesis in medulloblastoma. It will not only have scientific merits but also could be of practical value in treating patients with the devastating malignant brain tumor of childhood.